This application is a 371 of PCT/FR01/00980 Apr. 2, 2001.
A subject-matter of the present invention is novel indolin-2-one derivatives, a process for their preparation and the pharmaceutical compositions comprising them. These novel derivatives are powerful and selective ligands of the oxytocin receptors and can thus be used as an active principle in pharmaceutical compositions, in particular in the obstetric or gynaecological field. Oxytocin (OT) is a hormone excreted by the neurohypophysis with a cyclic nonapeptide structure similar to that of arginine vasopressin (AVP). The oxytocin receptors are essentially found on the smooth muscle of the uterus and on the myoedithelial cells of the mammary glands. Thus, oxytocin plays an important role in parturition since it is involved in the contraction of the uterine muscle and in lactation. Furthermore, oxytocin receptors are also located in other peripheral tissues and in the central nervous system; oxytocin can thus have effects in the cardiovascular, renal, endocrinal or behavioural fields.
Indolin-2-one derivatives have been disclosed in some patent applications as ligands of the vasopressin receptors and possibly of the oxytocin receptors; mention may be made of Patent Applications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO 97/15556 and WO 98/25901. To date, no indolin-2-one derivative has been disclosed as a powerful and selective ligand of oxytocin receptors.
It has now been found that certain indolin-2-one derivatives are powerful and selective ligands of oxytocin receptors.
Thus, according to one of its aspects, the present invention relates to novel indolin-2-one derivatives in the form of a pure enantiomer or a mixture of enantiomers of formula: 
in which:
R0 represents a group chosen from: 
in which:
Z1 represents a chlorine, bromine, iodine or fluorine atom or a (C1-C4)alkyl, (C1-C4)alkoxy or trifluoromethyl group;
Z2 represents a hydrogen, chlorine, bromine, iodine or fluorine atom or a (C1-C4)alkyl, (C3-C5)cycloalkyl, (C1-C4)alkoxy, (C3-C5) cycloalkoxy or (C1-C4)polyfluoroalkyl group;
R5 represents T1W in which T1 represents xe2x80x94(CH2)m, it being possible for m to be equal to 0 or 1, and W represents a hydrogen atom or a hydroxycarbonyl (or carboxyl), (C1-C4)alkoxycarbonyl, 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl group,
or else W represents an xe2x80x94NR6R7 group in which R6 and R7 represent, independently of one another, a hydrogen atom, a (C1-C4)alkyl group, a (C1-C4)alkylsulphonyl group or a phenylsulphonyl group in which the phenyl group can be mono-, di- or trisubstituted by Z5; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally substituted by a (C1-C4)alkyl group or an oxo; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the 4-position by a Z3 substituent; or else R6 and R7 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z4;
or else W represents an xe2x80x94NR8COR9 group in which R8 represents a hydrogen atom or a (C1-C4)alkyl group and R9 represents a hydrogen atom or a (C1-C4)alkyl, benzyl, pyridyl or phenyl group, it being possible for the said phenyl group to be mono-, di- or trisubstituted by Z5; or else R9 represents an xe2x80x94NR10R11 group in which R10 and R11 represent, independently of one another, a hydrogen atom or a (C1-C4)alkyl [lacuna] or else R10 and R11 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl, piperidyl or morpholinyl group optionally substituted by a (C1-C4)alkyl group; or else R9 represents a pyrrolidin-2-yl or -3-yl or piperid-2-yl, -3,-yl or -4-yl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z7; or else R9 represents a xe2x80x94T2xe2x80x94R12 or xe2x80x94T2xe2x80x94COR12 group in which T2 represents xe2x80x94(CH2)nxe2x80x94, it being possible for n to be equal to 1, 2, 3 and 4, and R12 represents a (C1-C4)alkoxy or xe2x80x94NR10R11 group, R10 and R11 being as defined above;
or else W represents a xe2x80x94CONR13R14 group in which R13 represents a hydrogen atom or a (C1-C4) alkyl, (C3-C7) cycloalkyl, monofluoro(C1-C4)alkyl or polyfluoro(C1-C4)alkyl group and R14 represents a hydrogen atom, a (C1-C4)alkyl group, a phenyl group optionally substituted by Z5, a xe2x80x94T4xe2x80x94R15 group in which T4 represents xe2x80x94(CH2)q, with q equal to 1, 2, 3 or 4, and R15 represents a hydroxyl group, a (C1-C4)alkoxy group, a (C1-C4)alkoxycarbonyl group, a (C1-C4)alkoxycarbonylamino group, a phenyl group optionally mono- or disubstituted by Z5, a pyrid-2-yl, -3-yl or -4-yl, or an xe2x80x94NR16R17 group in which R16 and R17 represent, independently of one another, a hydrogen atom or a (C1-C4)alkyl [lacuna] or else R16 and R17 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4)alkyl group or else R16 and R17 form, with the nitrogen atom to which they are bonded, a piperazinyl group optionally substituted in the 4-position by a Z3 substituent or else R16 and R17 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z5, it being understood that, when q=1, R15 is other than hydroxyl, (C1-C4)alkoxy, (C1-C4)alkoxycarbonylamino or xe2x80x94NR16R17; or else R13 and R14 form, with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4)alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z3 substituent; or else R13 and R14 form, with the nitrogen atom to which they are bonded, an azetidinyl, pyrrolidinyl, piperidyl or hexahydroazepinyl group, the said pyrrolidinyl, piperidyl and hexahydroazepinyl groups optionally being mono- or disubstituted by Z8;
or else W represents an OR18 group in which R18 represents a hydrogen atom or a (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl or xe2x80x94T3xe2x80x94R19 group in which T3 represents xe2x80x94(CH2)pxe2x80x94, it being possible for p to be equal to 2 or 3, and R19 is chosen from the hydroxyl, triphenylmethoxy or xe2x80x94NR20R21 groups in which R20 represents a hydrogen atom or a (C1-C4)alkyl group and R21 represents a hydrogen atom or a (C1-C4)alkyl, tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or else R20 and R21 form,,with the nitrogen atom to which they are bonded, a morpholinyl group optionally mono- or disubstituted by a (C1-C4)alkyl group or a piperazinyl group optionally substituted in the 4-position by a Z3 substituent, or else R20 and R21 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl and piperidyl groups optionally being substituted by Z5;
Z3 represents a (C1-C4)alkyl, pyridyl, phenyl, (C1-C4)alkylcarbonyl or (C1-C4)alkoxycarbonyl group;
Z4 represents an oxo, a fluorine atom, a hydroxyl, a (C1-C4)alkyl, a benzyl, an amino, a (C1-C4)alkylamino, a di(C1-C4)alkylamino, a (C1-C4)alkoxy, a (C1-C4)alkoxycarbonyl or a (C1-C4)alkoxycarbonylamino;
Z5 represents a chlorine, bromine, iodine or fluorine atom, a hydroxyl group, a (C1-C4)alkyl group or a (C1-C4)alkoxy group;
Z7 represents a fluorine atom, a hydroxyl group, a hydroxy(C1-C4)alkyl group, a (C1-C4)alkyl [lacuna], a (C1-C4)alkoxy [lacuna] or a (C1-C4)alkylcarbonyl [lacuna];
Z8 represents a fluorine atom or a hydroxyl, (C1-C4)alkyl, (C3-C6)cycloalkyl, benzyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycarbonylamino, (C3-C6)cycloalkoxy, hydroxycarbonyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxy or xe2x80x94CONR23R24 group in which R23 and R24 represent, independently of one another, a hydrogen atom, a (C1-C4)alkyl, a monofluoro(C1-C4)alkyl or a polyfluoro(C1-C4)alkyl, or else R23 and R24 form, with the nitrogen atom to which they are bonded, a pyrrolidinyl or piperidyl group, the said pyrrolidinyl or piperidyl groups optionally being substituted by Z3 or a difluoromethylidene; 
Z6 represents a chlorine atom or a (C1-C4)alkyl or (C1-C4) alkoxy group;
R1 represents a (C1-C4)alkyl group optionally comprising a double or a triple bond, a (C1-C4)alkoxycarbonyl group, a phenyloxycarbonyl group or a T1xe2x80x94R22 group in which T1 is as defined above and R22 represents a hydroxyl or (C1-C4)alkoxy group;
R2 and R4 represent, independently of one another, a hydrogen, chlorine or fluorine atom or a (C1-C4)alkyl or (C1-C4)alkoxy group;
R3 represents a chlorine or fluorine atom or a (C1-C4)alkyl, (C1-C4)alkoxy, hydroxyl, (C1-C4)carbamoyl, (C1-C4)alkylcarbonylamino, nitro, cyano, trifluoromethyl, amino, (C3-C6)cycloalkylamino, (C1-C4)alkylamino, di(C1-C4) alkylamino, tri(C1-C4)alkylammonium Axe2x88x92, Axe2x88x92 being an anion, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or hexahydroazepin-1-yl group;
X and Y represent, independently of one another, a hydrogen, chlorine, bromine, iodine or fluorine atom or a (C1-C4)alkoxy or trifluoromethoxy group; and to their pharmaceutically acceptable salts, their solvates and their hydrates.
The term xe2x80x9calkylxe2x80x9d is understood to mean a saturated, linear or branched, monovalent hydrocarbonaceous radical.
The term xe2x80x9c(C1-C4)alkylxe2x80x9d is understood to mean an alkyl radical comprising from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
The term xe2x80x9calkylenexe2x80x9d is understood to mean a saturated, linear or branched, bivalent hydrocarbonaceous radical.
The term xe2x80x9calkoxyxe2x80x9d is understood to mean an O-alkyl radical.
The term xe2x80x9canion Axe2x88x92xe2x80x9d is understood to mean, for example, a Clxe2x88x92, Br, Ixe2x88x92 or CH3SO4xe2x88x92.
The term xe2x80x9cdi(C1-C4)alkylaminoxe2x80x9d is understood to mean an amino radical substituted by two alkyl radicals which can be identical or different. In the same way, for tri(C1-C4)ammoniums, the alkyl radicals can be identical or different.
The salts of the compounds according to the invention are prepared according to techniques which are well known to a person skilled in the art. The salts of the compounds of formula (I) according to the present invention comprise those with inorganic or organic acids, which make possible suitable separation or crystallization of the compounds of formula (I), and pharmaceutically acceptable salts. Mention may be made, as appropriate acid, of: picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulphonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, the hydrobromide, the sulphate, the hydrogensulphate, the dihydrogenphosphate, the maleate, the fumarate, the 2-naphthalenesulphonate or the para-toluenesulphonate, the hydrochloride being preferred.
When a compound according to the invention exhibits one or more asymmetric carbons, the optical isomers of this compound form an Integral part of the invention. When a compound according to the invention exhibits stereoisomerism, for example of axial-equatorial or Z-E type, the invention comprises all the stereoisomers of this compound.
The present invention comprises the compounds of formula (I) in the form of pure isomers but also in the form of a mixture of isomers in any proportion.
The compounds (I) are isolated in the form of pure isomers by conventional separating techniques: use may be made, for example, of fractional recrystallizations of a salt of the racemate with an optionally active acid or base, the principle of which is well known, or conventional chromatography techniques on a chiral or nonchiral phase.
The compounds of formula (I) above also comprise those in which one or more hydrogen, carbon or halogen, in particular iodine, chlorine or fluorine, atoms have been replaced by their radioactive isotope, for example tritium or carbon-14. Such labelled compounds are of use in research, metabolic or pharmacokinetic studies or in biochemical assays as receptor ligand.
The functional groups possibly present in the molecule of the compounds of formula (I) and in the reaction intermediates can be protected, either in permanent form or in temporary form, by protective groups which ensure unequivocal synthesis of the expected compounds. The protection and deprotection reactions are carried out according to techniques well known to persons skilled in the art. The term xe2x80x9ctemporary protective group for amines or alcoholsxe2x80x9d is understood to mean protective groups such as those described in Protective Groups in organic Synthesis, Greene T. W. and Wuts P. G. M., published by Wiley Intersciences, 1999, and in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag.
Mention may be made, for example, of temporary protective groups for amines: benzyls, carbamates (such as tert-butyloxycarbonyl, which can be cleaved in acidic medium, or benzyloxycarbonyl, which can be cleaved by hydrogenolysis); for carboxylic acids: alkyl esters (such as methyl, ethyl or tert-butyl esters, which can hydrolyse in basic or acidic medium) and benzyl esters, which can be hydrogenolysed; for alcohols or for phenols, such as tetrahydropyranyl, methyloxymethyl, methylethoxymethyl, tert-butyl and benzyl ethers; or for carbonyl derivatives, such as linear or cyclic acetals, like, for example, 1,3-dioxane-2-yl or 1,3-dioxolan-2-yl; and reference may be made to the well known general methods described in the abovementioned Protective Groups.
A person skilled in the art will be in a position to choose the appropriate protective groups. The compounds of formula (I) can comprise precursor groups of other functional groups which are subsequently generated in one or more other stages.
One family of compounds according to the invention is composed of indolin-2-one derivatives in the form of a pure enantiomer or of a mixture of enantiomers of formula: 
in which:
R0 represents 
Z1, Z2, R1, R2, R3, R4, R5, Y and X are as defined for (I), and their pharmaceutically acceptable salts, their solvates and their hydrates.
According to another of its aspects, the invention relates to the compounds of formula: 
in which R1 represents a methyl or hydroxyl group and R0, R2, R3, R4, X and Y are as defined for (I); in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
A subfamily of the compounds according to the invention is composed of the compounds of formula: 
in which R1 represents a methyl or hydroxyl group and R0, R3, R4 and X are as defined for (I); in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
Another subfamily of the compounds according to the invention is composed of the compounds of formula: 
in which R1 represents a methyl or hydroxyl group and R0 and R3 are as defined for (I); in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
Another subfamily of the compounds according to the invention is composed of the compounds of formula: 
in which R1 represents a methyl or hydroxyl group and R0 is as defined for (I); in the form of a pure enantiomer or of a mixture of enantiomers, and their pharmaceutically acceptable salts, their solvates and their hydrates.
Among these compounds of formula (I), (Ia), (Ib), (Ic) and (Id), those in which R0 represents the group: 
in particular the group: 
in which R5 is as defined for (I), constitute another aspect of the invention.
Among the latter compounds, those in which R1 represents a methyl group constitute another aspect of the invention.
According to another of its aspects, the invention relates to the compounds chosen from: 5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 1);
5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylamino)-2-methoxybenzyl]-3-methylindolin-2-one (Example 56);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}acetamide (Example 70);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methylbutanamide (Example 73);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}benzamide (Example 74);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}nicotinamide (Example 76);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-2-methoxyacetamide (Example 77);
Methyl 3-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]anilino}-3-oxopropanoate (Example 78);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-3-methoxypropanamide (Example 81);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylacetamide (Example 87);
N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-N-methylmethane-sulphonamide (Example 97);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-diethylbenzamide (Example 102);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N,N-dimethylbenzamide (Example 109);
5-Chloro-3-[2-chloro-5-(1-piperidylcarbonyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 112);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethylbenzamide (Example 114);
5-Chloro-3-(2-chloro-5-{[2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}phenyl)-1-(2,4-dimethoxy-benzyl)-3-methylindolin-2-one (Example 119);
5-Chloro-3-{2-chloro-5-[(2-methyl-1-piperidyl)-carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 122);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-methylbenzamide (Example 124);
Methyl 1-{4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl}-2-piperidine-carboxylate (Example 131);
5-Chloro-3-{2-chloro-5-[(4-hydroxy-1-piperidyl)-carbonyl]phenyl}-1-(2,4-dimethoxybenzyl)-3-methyl-indolin-2-one (Example 134);
5-Chloro-3-{2-chloro-5-[(2-methoxyethoxy)methyl]-phenyl}-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 142);
5-Chloro-3-[2-chloro-5-(4-morpholinylmethyl)phenyl]-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 148);
5-Chloro-3-(2-chloro-5-{[2-(4-morpholinyl)ethoxy]-ethyl}phenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one (Example 152);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-3-hydroxypiperidine (Example 194);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-3-hydroxypiperidine (Example 195);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-methoxypiperidine (Example 166);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-4-ethoxypiperidine (Example 167);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R,S)-2,6-dimethylpiperidine (Example 189);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-ethoxycarbonylpiperidine (Example 175);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-N,N-dimethyl-aminocarbonylpiperidine (Example 169);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-(N-methyl-N-2,2,2-trifluoroethylaminocarbonyl)piperidine (Example 170);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(R)-2-pyrrolidinocarbonylpiperidine (Example 168);
1-[4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]benzoyl]-(S)-2-methylpiperidine (Example 174);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-phenylethyl)benzamide (Example 185);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(4-pyridylmethyl)benzamide hydrochloride (Example 188);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(3-pyridylmethyl)benzamide (Example 201);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyridylmethyl)benzamide (Example 200);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-methoxyethyl)benzamide (Example 184);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-dimethylaminoethyl)-benzamide hydrochloride (Example 177);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-morpholinoethyl)-benzamide (Example 178);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-pyrrolidinoethyl)-benzamide hydrochloride (Example 182);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-piperidinoethyl)-benzamide hydrochloride (Example 183);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2-hydroxyethyl)benzamide (Example 198);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[2-(pyrid-4-yl)ethyl]-benzamide hydrochloride (Example 179);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-(2,2,2-trifluoroethyl)-benzamide (Example 180);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-methyl-N-(2,2,2-trifluoroethyl)-benzamide (Example 171);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-isopropylbenzamide (Example 187);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-(2-dimethylaminoethyl)-N-(2,2,2-trifluoroethyl)benzamide hydrochloride (Example 202);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-cyclohexylbenzamide (Example 192);
4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]-N-ethyl-N-[3-(pyrid-4-yl)propyl]-benzamide (Example 204);
in the form of a pure enantiomer or of a mixture of enantiomers, and to their pharmaceutically acceptable salts, their solvates and their hydrates.
The compound of formula (I) can be prepared according to the following Scheme 1: 
In this scheme, R0, R1, R2, R3, R4, X and Y are as defined for (I) and, for (Ip), Rxe2x80x20, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24, Xxe2x80x2 and Yxe2x80x2 respectively represent either R0, R1, R2, R3, R4, X and Y as defined for (I) or a precursor group for R0, R1, R2, R3, R4, X and Y, it being understood that Rxe2x80x21 is other than hydrogen.
Another subject-matter of the present invention is a preparation process for the compounds of formula (I), characterized in that:
a) a compound of formula: 
in which X, Y, R0 and R1 are as defined for (I), is reacted in the presence of a base with a halide of formula: 
in which Hal represents a halogen atom and R2, R3 and R4 are as defined for (I);
b) or else, when R1 represents an electrophilic group, the compound of formula: 
in which R0, R2, R3, R4, X and Y are as defined for (I), is converted by the action of a derivative R1xe2x80x94Z, in which Z represents a leaving group, in the presence of a base;
c) or else, when R1=OH, an isatin derivative of formula: 
in which R2, R3, R4, X and Y are as defined for (I), is reacted with an organometallic derivative R0xe2x80x94M or R0MgHal, R0 being as defined for (I), M being a metal atom and Hal being a bromine or iodine atom;
d) or else the compound of formula: 
in which Rxe2x80x20, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24, Xxe2x80x2 and Yxe2x80x2 respectively represent either R0, R1, R2, R3, R4, X and Y as defined for (I) or a precursor group for R0, R1, R2, R3, R4, X and Y, is subjected to a subsequent treatment to convert any one of the Rxe2x80x20, Rxe2x80x21, Rxe2x80x22, Rxe2x80x23, Rxe2x80x24, Xxe2x80x2 and Yxe2x80x2 groups to respectively R0, R1, R2, R3, R4, X or Y as defined for (I), according to reactions well known to a person skilled in the art.
The reaction described in a) is preferably carried out with a compound (1) in which Hal=Cl or Br using, as base, a metal hydride, such as sodium hydride, or an alkali metal alkoxide, such as potassium tert-butoxide, in an anhydrous solvent, such as dimethylformamide or tetrahydrofuran.
In the reaction described in b), the term xe2x80x9cleaving groupxe2x80x9d is understood to mean, for example, a halogen atom, such as chlorine, bromine or iodine, or alternatively a sulphonic ester group, such as para-toluenesulphonate. The compound (III) is preferably reacted with a halide R1-Hal, R1 being as defined for (I) and Hal being a halogen atom, preferably an iodine atom, in the presence of a base; the reaction will be carried out, for example, in the presence of a base, such as an alkali metal alkoxide, for instance potassium tert-butoxide, in an ethereal solvent, such as tetrahydrofuran, or alternatively in the presence of a carbonate, such as sodium, potassium or caesium carbonate, in a solvent such as dimethylformamide or acetonitrile.
Advantageously, in the reaction described in c), the compound of formula (IV) is reacted with a magnesium derivative R0Mg-Hal, R0 being as defined for (I) or (Ip) and Hal being a bromine or preferably iodine atom, or alternatively the compound (IV) is reacted with a derivative R0M in which M is preferably a lithium atom. This derivative R0Li is obtained either by direct lithiation, for example by the action of butyllithium or lithium diisopropylamide according to Heterocycles, 1993, 35(1), 151-169, or by a halogenlithium exchange reaction according to Organolithium Methods, Pergamon Press, New York, 1988 or J. Am. Chem. Soc., 1956, 2217. These reactions are preferably carried out in an anhydrous solvent, such as diethyl ether or tetrahydrofuran.
The conversion of the compound (Ip), the precursor of the compound (I), described in d) is carried out according to conventional techniques.
Furthermore, the compounds (I) can be obtained from another compound,(I) by conversion of one of the R0, R1, R2, R3, R4, X or Y substituents, in particular R0, R1 or R3 substituents. For example:
the compounds (I) in which R3=xe2x80x94NH2 can be obtained by reduction of the corresponding compounds (I) in which R3=xe2x80x94NO2, for example by the action of hydrochloric acid in the presence of tin in an alcohol, such as ethanol;
the compounds (I) in which R3 represents a (C1-C4)alkylamino or di(C1-C4)alkylamino group can be obtained from the corresponding compounds (I) in which R3=xe2x80x94NH2 by a reductive amination reaction. Reference may be made to J. Org. Chem., 1996, 61, 3849-3862 and the reaction can be carried out by the action of a (C1-C4)alkyl aldehyde in the presence of sodium triacetoxyborohydride or alternatively reference may be made to J. Am. Chem. Soc., 1974, 96(25), 7812 and the reaction can be carried out by the action of a (C1-C4)alkyl acid in the presence of sodium borohydride. Use may also be made of conventional N-alkylation reactions, for example by reacting the amino group with a (C1-C4)alkyl halide in the presence of dimethylformamide and potassium carbonate;
the compounds (I) in which R3 represents a (C1-C4)alkoxy can be obtained from the corresponding compounds (Ip) in which Rxe2x80x23=OH by a conventional O-alkylation reaction, for example by the action of a (C1-C4)alkyl halide in the presence of dimethylformamide and of caesium or potassium carbonate;
the compounds (I) in which R3 represents a (C1-C4)alkylcarbonylamino group can be obtained from the corresponding compounds (I) in which R3=xe2x80x94NH2 by a conventional acylation, such as the action of a (C1-C4)alkyl acid chloride in the presence of a base, such as triethylamine, in a solvent, such as dichloromethane;
the compounds (I) in which R3 represents a cyclic amine or a morpholin-4-yl can be obtained from the corresponding compounds (I) in which R3=xe2x80x94NH2 according to the method described in Tetrahedron, 1989, 45(3), 629-636.
the compounds of formula (I) in which R0 represents a group: 
can be obtained from the corresponding compounds of formula (I) by conversion of the R5 group according to conventional reactions, for example alkylation, acylation, oxidation, reduction or amination reactions, well known to a person skilled in the art.
The compounds (III) are prepared by dehalogenation of the compounds of formula: 
in which R0, R2, R3, R4, X and Y are as defined for (I) and Hal represents a chlorine, bromine or iodine atom, for example by the action of a hindered lithium dialkylamide, such as lithium diisopropylamide (LDA), by analogy with the method described by N. Newcom et al. in J. Am. Chem. Soc., 1990, 5186-5193.
The compound (Ixe2x80x2) is, for example, obtained by conversion of the corresponding compound (I) in which R1=OH by the action of a halogenated derivative, for example of acid halide type. Mention may be made, as chlorinated derivative, of SOCl2.
The compound (IV) is generally obtained by reaction of the compound (l) with the isatin derivative of formula: 
in which X and Y are as defined for (I), under the same conditions as those described above for the preparation of the compound (I) from the compound (II). The isatin derivatives (2) are commercially available compounds or are prepared according to the methods described in Tetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron Letters, 1994, 35, 7303-7306; J. Org. Chem., 1977, 42, 1344-1348 and Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58.
The compounds (II) can be synthesized according to various methods disclosed in particular in Patent Applications EP 526 348 and WO 95/18105.
Some routes for the production of the compounds (II) are illustrated in Scheme 2: 
The term xe2x80x9cnucleophilic R1xe2x80x9d is understood to mean a (C1-C4) alkoxy group.
The compound (II) in which R1 represents an electrophilic group, for example a (C1-C4)alkyl group, can be prepared from the compounds of formula: 
in which R0, X and Y are as definded for (I), by reaction with a derivative R1xe2x80x94Z in which Z represents a leaving group, under the same conditions as those described above for the transformation of the compound (III) to the compound (I).
The compound (V) is generally synthesized:
either by dehydroxylation of the corresponding compound (II) in which R1=OH by the action of tin chloride in acidic medium, according to the method described in Tetrahedron, 1996, 52(20), 7003-7012, or by the action of triethylsilane, according to Bioorganic and Medicinal Letters, 1997, 7(10), 1255-1260;
or by a cyclization reaction in a strong acid medium, such as, for example, sulphuric acid, of the compound of formula: 
in which R0, X and Y are as defined for (I), this compound (VII) itself being obtained by a condensation reaction between an xcex1-hydroxyacetic acid derivative of formula: 
R0 being as defined for (I), with an aminobenzene of formula: 
in which X and Y are as defined for (I).
The compounds (3) are commercially available or are conventionally synthesized.
The compounds of formula (VIII) are commercially available or are synthesized according to methods well known to a person skilled in the art. Reference may in particular be made to J. Med. Chem., 1987, 30(8), 1447.
Other reactions can also lead to the compounds (V). Mention may be made of:
the Brunner reaction described in Tetrahedron, 1986, 42(15), 4267-4272: 
the cyclization reaction in the presence of formic acid described in J. Chem. Soc. Perkin Trans., 1986, 1, 349-360: 
the following cyclization reactions: 
according to J. Am. Chem. Soc., 1985, 107(2), 435-443: 
according to Tetrahedron, 1996, 52(20), 7003-7012.
The compounds (II) in which R1 represents a (C1-C4)alkoxy group are obtained from the compounds of formula: 
in which R0, X and Y are as defined for (I) and Hal represents a halogen atom, for example a chlorine atom, by the action of the corresponding alcohol R1H.
The compound (VI) is prepared from the corresponding compound (II) in which R1=OH by reaction with thionyl chloride in the presence of pyridine in dichloromethane.
The compounds (II) in which R1=OH are generally prepared from the corresponding isatin of formula: 
in which X and Y are as defined for (I), according to the method described above for the preparation of the compounds (I) in which R1=OH from the compounds (IV).
When R1 does not represent a hydroxyl group, the compounds (II) can also be prepared according to Scheme 3 below: 
In this Scheme 3, R0, R1, X and Y are as defined for (I), R1 does not represent a hydroxyl group and M represents, for example, a lithium atom or MgHal, Hal being a halogen atom.
The transformation of the compound (X) to the compound (IX) to give the compound (II) is carried out in particular according to the method described in J. Chem. Soc., 1957, 1928.
The benzyl halides (1) are known or are prepared according to known methods. Mention may be made, for example, of J. V. Rajanbabu, J. Org. Chem., 1986, 51, 1704-1712 and the publications cited in EP 636 609.
Generally, the halomethylbenzene derivatives (1) can be prepared by the action of N-halosuccinimides on the corresponding methylbenzene derivatives and according to EP 229 566. The reaction is carried out in a solvent, such as carbon tetrachloride, in the presence of dibenzoyl peroxide. A halomethylbenzene derivative can also be prepared from a corresponding hydroxymethylbenzene derivative by reaction with phosphorus tribromide in diethyl ether or by reaction with thionyl chloride.
At any stage in the process, an intermediate compound of (IIp), (IIIp) or (IVp) type, in which at least one of the substituents is replaced by one of its precursor groups, can be formed intermediately. These compounds (IIp), (IIIp) and (IVp) will be converted by conventional reactions into (II), (III) and (IV) respectively. A person skilled in the art will be in a position to adapt the abovementioned reactions to the compounds (IIp), (IIIp) and (IVp).
The compounds according to the invention have formed the subject of biochemical and pharmacological studies. The affinity of the compounds according to the invention for oxytocin receptors was determined in an in vitro binding test using the method described by J. Elands et al. in Eur. Pharmacol., 1987, 147, 192-207. This method consists in studying in vitro the displacement of a radioiodinated oxytocin analogue at the oxytocin receptors in a membrane preparation of human uterine oxytocin receptors. The IC50 values (concentration which inhibits 50% of the binding of the radioiodinated oxytocin analogue to its receptors) are low and vary from 10xe2x88x9210 to 10xe2x88x926 M in the latter test.
The affinity of the compounds according to the invention for human vasopressin V1a receptors (method described by M. Thibonnier et al. in J. Biol. Chem., 1994, 269, 3304-3310), V1b receptors (method described by T. Sugimoto et al. in J. Biol. Chem., 1994, 269, 27088-27092) and V2 receptors (method described by M. Birnbaumer et al. in Nature (Lond.), 1992, 357, 333-335) has also been studied. The compounds studied have little or no affinity for the V1a, V1b and V2 receptors. By way of indication, the compound of Example 1 exhibits an IC50 of less than 50 nM, the IC50 values with respect to the V1a, V1b and V2 receptors being greater than 1 xcexcM.
The agonist or antagonist nature of the compounds is determined in vitro in a test for the measurement of intracellular calcium with respect to cells expressing human oxytocin receptors according to the general technique described in Am. J. Physiol., 268 (Heart Circ. Physiol., 37), 1995, H404-H410.
When the compounds according to the invention behave as antagonists, their IC50 is advantageously between 0.5 xcexcM and 0.5 nM. By way of example, the dextrorotatory enantiomer of Example 1 is an antagonist with an IC50 of 3.2xc2x11.9 nM.
The compounds according to the invention, powerful and selective ligands of oxytocin receptors, are particularly advantageous in the prevention and/or treatment of oxytocin-dependent disorders. The compounds according to the present invention can either mimic or inhibit the effects of oxytocin.
They will be particularly advantageous in cicatrization, in analgesia and anxiolysis (prevention of pain and anxiety), depression, schizophrenia, autism, obsessive compulsive syndrome, in maternal behaviour (facilitation of mother-child recognition and acceptance) and social behaviour, memory, regulation of food and drink intake, dependence on drugs, weaning and sexual motivation. They can be advantageously used in disorders of the urogenital sphere, in particular in the obstetric and gynaecological fields, in particular as uterine relaxant or tocolytic agent or for controlling contractions of the uterus before pregnancy has arrived at term, for controlling prenatal labour or for controlling preparatory labour for the purpose of a caesarean delivery, for solving problems of sterility or fertility, controlling births (in particular veterinary use), controlling oestrus, the halting of breast feeding, weaning, or embryo transfer and implantation; treating endometriosis, dysmenorrhoea and urinary stress or urgency incontinence, benign prostate hypertrophy and erectile dysfunctions, hypertension, hyponatraemia, cardiac insufficiency, atherosclerosis or angiogenesis, and regulating the storage of fat by the adipocyte.
Furthermore, given the role of oxytocin in controlling luteinizing hormone (J. J. Evans, J. Endocrin., 1996, 151, 169-174), the compounds of the invention can be used to induce contraception.
Furthermore, the compounds according to the invention can be used for their antitumour effects in oxytocin-secreting tumours, in particular breast and prostate cancers.
The use of the compounds according to invention for the prevention and/or the treatment of the abovementioned conditions and for the preparation of medicaments intended to treat these conditions forms an integral part of the invention.
Another subject-matter of the present invention is thus pharmaceutical compositions comprising a compound according to the invention or a pharmaceutically acceptable salt, solvate or hydrate of the latter and suitable excipients. The said excipients are chosen according to the pharmaceutical form and the method of administration desired: oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular. The pharmaceutical compositions are prepared according to techniques known to a person skilled in the art.
In order to obtain, the desired prophylactic or therapeutic effect, each unit dose can comprise from 0.5 to 1 000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical vehicle. This unit dose can be administered 1 to 5 times daily, so as to administer a daily dosage of 0.5 to 5 000 mg, preferably from 1 to 2 500 mg.
The compounds according to the invention can also be used for the preparation of compositions for veterinary use intended to regulate births.
The compounds according to the invention can also be used for the preparation of cosmetic compositions. These formulations can be provided in the form of a cream for topical use and will be intended to control lipolysis.
The compositions of the present invention can comprise, in addition to the products of formula (I) above or their pharmaceutically salts, solvates and hydrates, [lacuna] and for example active principles which may be of use in the treatment of the disorders or conditions indicated above. Thus, another subject-matter of the present invention is pharmaceutical compositions comprising several active principles in combination, one of which is a compound according to the invention. In particular, the present invention relates to pharmaceutical compositions comprising a compound according to the invention, an antagonist of oxytocin receptors, with a V1a antagonist compound. This type of composition will be of particular use in the treatment of dysmenorrhoea or endometriosis or the control of premature labour and for controlling preparatory labour for the purpose of a caesarean delivery.
Another subject-matter of the invention is products comprising an antagonist of oxytocin receptors as defined above and an antagonist of vasopressin V1a receptors for simultaneous or separate use or use spread out over time in the treatment of dysmenorrhoea or endometriosis or the control of premature labour and for controlling preparatory labour for the purpose of a caesarean delivery.